Activer les gènes responsables de multiples enzymes perdues.

Kidney cancer, one of the ten most prevalent malignancies in the world, has increased in incidence over the last decade, likely due to rising obesity rates. The most common subtype of this cancer is "clear cell" renal cell carcinoma (ccRCC), which exhibits multiple metabolic abnormalities, such as highly elevated stored sugar and fat deposition.

By integrating data on the function of essential metabolic enzymes with genetic, protein, and metabolic abnormalities associated with ccRCC, researchers at the Perelman School of Medicine at the University of Pennsylvania determined that enzymes important in multiple pathways are universally depleted in ccRCC tumors. They published their findings this week in Cell Metabolism.

"Kidney cancer develops from an extremely complex set of cellular malfunctions," said senior author Celeste Simon, PhD, the scientific director of the Abramson Family Cancer Research Institute and a professor of Cell and Developmental Biology. "That's why we approached studying its cause from many perspectives."

Using human tissue provided by the National Cancer Institute's Cooperative Human Tissue Network and Penn Medicine physicians Naomi Haas, MD, an associate professor of Hematology/Oncology, and Priti Lal, MD, an associate professor of Pathology and Laboratory Medicine, the team found that the expression of certain enzymes is strongly repressed in ccRCC tumors. For example, reduced activity of one enzyme, arginase, promotes ccRCC tumor growth through at least two distinct biochemical pathways. One is by conserving a critical molecular cofactor and the second is by avoiding toxic accumulation of organic compounds. The enzymes whose activities are depressed are involved in the breakdown of urea, a byproduct of protein being used in the human body. In addition, loss of these enzymes results in decreased ability of the immune system to eradicate these tumors.

"Pharmacological approaches to restore the expression of urea cycle enzymes would greatly expand treatment options for ccRCC patients, whose current therapies only benefit a small subset," Simon said.

In the future, the researchers aim to test such epigenetic drugs as HDAC and DNA methylase inhibitors to turn on genes for multiple lost enzymes in renal cancer. The study was completed by researchers at both Penn Medicine and Children's Hospital of Philadelphia who specialize in studying metabolic abnormalities in children.

The research group of Prof. Antonio M. Echavarren at ICIQ has designed and synthetized a series of analogues of (-)-Englerin A that are highly selective and effective in the growth-inhibition of renal cancer cells.

The molecule (-)-Englerin A was isolated in 2009 from the bark of the east African plant Phyllanthus engleri by scientists at the US National Cancer Institute, and has received a lot of attention because of its ability to kill kidney cancer cells selectively. Kidney cancer is often treated surgically and responds poorly to existing drugs, which can have serious side effects. So, new drugs based on (-)-englerin A could help improve outcomes for patients. Several total syntheses have been reported to date and two distinct mechanisms for Englerin A's anticancer activity have been proposed.

In 2010 the research group of Prof. Echavarren achieved the total synthesis of (-)-Englerin A starting from inexpensive geraniol and using as the key transformation a gold-catalyzed cycloaddition invented by his group. The synthesis was efficient and easily scalable and, what is more important, the intermediate obtained after the gold-catalyzed cycloaddition opened the way for the synthesis of new and useful derivatives.

Taking the previous total synthesis of the natural product as starting point, Echavarren's group has synthetized a set of analogues with great structural diversity. An important point to note is that the original synthesis has been scaled-up to the multigram scale. "We have developed potent anticancer compounds inspired on the structure of englerin as a final result of curiosity-driven research in gold chemistry" -says Prof. Echavarren.

The biological study of the first series revealed that the derivatives with a double bond between C4 and C5 were more active against renal cancer and worthy of further exploration. Then, a second library of compounds maintaining the unsaturation between C4 and C5 was prepared. The study of the new series of compounds revealed and interesting selectivity profile and very good growth inhibition potency in some of the renal cancer cell lines. The structure-activity relationship findings of this study open promising ways in the fight against renal cancer and are being used in the design of more potent and bioavailable drug candidates against other cancer types.

The program initiated by basic research in the new field of gold catalysis led to the total synthesis of a biologically relevant molecule, opening the doorway to a practical solution for the synthesis of structurally simplified analogues, which were developed in the CSOL (Catalyst Selection and Optimization Laboratory) unit at ICIQ. This Technology Development Unit is oriented the valorization of research results developed at ICIQ in order to bridge the gap between research results and their application in industry. The biological studies have been carried out in the US National Cancer Institute (National Institute of Health, USA) by Prof. Beutler and collaborators.

Cancer chemotherapy can be a rough ride, in part because most of these drugs don't distinguish between what's cancerous and what's not. The chemicals attack all rapidly dividing cells, from cancer cells, to blood cells and the cells that make hair. However, drugs that target a biological phenomenon only found in cancer cells, such as the compound recently discovered by Stanford researchers, could efficiently fight the disease with minimal side effects. The finding will be published Aug. 3 in Science Translational Medicine.

"This study demonstrates an approach for selectively inhibiting the ability of cancer cells to take up glucose, which is a pretty powerful way of killing those cells," said senior study author Amato Giaccia, PhD, professor and director of radiation oncology.

The researchers focused their study on the most common form of kidney cancer in adults, renal cell carcinomas, which constitute almost 2 percent of all cancers in the United States, according to the Centers for Disease Control and Prevention. The disease is resistant to typical chemotherapies, and patients often have to have the affected kidney removed. Nearly 90 percent of these cancers carry a specific genetic mutation that leads to uncontrolled cell growth.

Les chercheurs ont pris le cancer du rein chez l'adulte comme cible.

"Most normal tissues in the body don't possess this mutation, so a drug that targets this vulnerability should be very specific for cancer cells," said Giaccia, who is also a member of the Stanford Cancer Institute.

With the help of the Stanford High-Throughput Bioscience Center, the team tested a library of 64,000 synthetic chemical compounds on tumor cells with that mutation and then looked for signs of cell death.

The screen produced two candidate cancer drugs, one reported by Giaccia in 2008, STF-62247, which is now in preclinical testing. The other, STF-31, described in the new study, kills cancer cells in a different way, so a combination of the two drugs would allow a multipronged attack. "Or, if a cancer becomes resistant to one compound, you have another option," said Denise Chan, PhD, former postdoctoral researcher at Stanford and co-first author of the new study.

Most renal cell carcinomas produce energy through a biochemical process called aerobic glycolysis, one that healthy cells don't typically require. The energy-making process is dependent on the cells' ability to take up glucose from their environment. "The cells that we are targeting are highly dependent on glucose transport for energy production," said Chan, who is now an assistant professor at UC-San Francisco. "This compound stops the cells from transporting glucose, so it starves them."

Renal cell carcinomas aren't the only cancer cells that are glucose gluttons. Many cancers turn up their rate of glucose import, a fact used by doctors to monitor cancers in live patients. Doctors can inject a radioactively labeled glucose and follow its uptake in the body with PET scanning. Using a similarly labeled glucose, the team found that STF-31 reduced the amount of glucose the cancer cells could ingest, thus robbing them of their energy source.

Les cellules du cancer du ne sont pas les seuls à être gournandes en glucose. Plusieurs cancers augment leur taux de glucose. C'est un fait utilisé par les docteurs pour surveiller le cancer de leurs patients. en utilisant un glucose semblable à ceux utilisés par les docteurs pour voir la progression du cancer, l'équipe de recherche a découvert que le STF-31 réduisait le montant de glucose ingérer par les cellules cancéreuses.The team also tested the compound in a mouse model of kidney cancer and found that STF-31 nearly halved the amount of glucose imported by tumors and slowed tumor growth. In mice, at least, the drug appears to have few side effects. Mice treated with the compound for 14 days had no apparent damage to their normal tissues: They maintained a normal immune system and normal numbers of blood cells. "The other major tissue that comes up when you think glucose transport is the brain, and we didn't see any toxicity with the brain," said Chan.

Further experiments showed that STF-31 binds directly to a glucose transporter, probably blocking the pore of the channel-like molecule, computational modeling predicts. The team hopes to find other cancer types that are dependent on the same glucose transporter. Palo Alto biotechnology company Ruga Inc., co-founded by Giaccia, has licensed the drug for preclinical testing. Giaccia is on the company's scientific advisory board; Chan serves as a consultant.

The study was funded by Action to Cure Kidney Cancer, the Cecile and Ken Youner Fund for Cancer Research, the Association for International Cancer Research, the Maurice Wilkins Centre for Biodiscovery and the National Cancer Institute.

Giaccia's work focuses on the von Hippel-Lindau tumor suppressor gene, or VHL gene, which normally slows tumor growth in humans but does not work in 75 percent of kidney tumor cells. Giaccia's team searched for a small molecule that would kill cancer cells when this VHL gene is broken. They found their weapon in a molecule called STF-62247.

As an added benefit, Giaccia said, patients treated with STF-62247 should not suffer some of chemotherapy's infamous side effects, like nausea and hair loss, because STF-62247 is not toxic to the entire body.

This study is one of the first to identify a trait unique to a certain form of cancer - in this case, kidney cancer's deficient VHL gene - and exploit it to defeat the disease, Chan said. She predicted other scientists soon would follow suit, looking for characteristics in other cancers that also could be manipulated.

Researchers' motivation could be twofold, the study's authors said: to find cures for deadly cancers, and to rein in the debilitating side effects caused by many current cancer treatments.

"These results can be extended far beyond kidney cancer," Chan said.

The findings also speak well for Stanford's High-Throughput BioScience Center, which opened in 2004. The results of this study are some of the first using the center's equipment.

The high-throughput equipment at Stanford can analyze thousands of molecules for their cytotoxicity at the same time, allowing researchers like those in Giaccia's lab to search for hidden genes and molecules that previously would have been quite laborious to find.

Without the center, "This work would not have been possible," said Stanford co-author Patrick Sutphin, MD. The findings have special significance for Sutphin, who worked with the Stanford team before moving on to his internship in medicine at Massachusetts General Hospital in Boston. In 1995, when Sutphin was a sophomore in college, his grandfather was diagnosed with kidney cancer and died three months later, he said.

The experience of losing his grandfather to kidney cancer helped motivate Sutphin to study the disease. His hope, Sutphin said, "is that one day our collective research will result in new drugs that are more effective than traditional drugs, and without the toxic side effects."

Other co-authors of the study include Stanford researcher and postdoctoral fellow Sandra Turcotte, PhD. The research was funded by a grant from the National Cancer Institute.